There is a close association between particular chromosomal abnormalities, e.g., chromosomal translocations, inversions, and deletions, and certain types of malignancy indicating that such abnormalities may have a causative role in the cancer process. Chromosomal abnormalities may lead to gene fusion resulting in chimeric oncoproteins, such as is observed in the majority of the tumors involving the myeloid lineage. Alternatively, chromosomal abnormalities may lead to deregulation of protooncogenes by their juxtaposition to a regulatory element active in the hematopoietic cells, such as is observed in the translocation occurring in the lymphocytic lineage (Virgilio et al., 1993, Proc. Natl. Acad. Sci. USA 90:9275-9279).
Non random chromosomal translocations are characteristic of most human hematopoietic malignancies (Haluska et al., 1987, Ann. Rev. Genet. 21:321-345) and may be involved in some solid tumors (Croce, 1987, Cell 49:155-156). In B and T cells, chromosomal translocations and inversions often occur as a consequence of mistakes during the normal process of recombination of the genes for immunoglobulins (Ig) or T-cell receptors (TCR). These rearrangements juxtapose enhancer elements of the Ig or TCR genes to oncogenes whose expression is then deregulated (Croce, 1987, Cell 49:155-156). In the majority of the cases, the rearrangements observed in lymphoid malignancies occur between two different chromosomes.
The TCL-1 locus on chromosome 14 band q32.1 is frequently involved in the chromosomal translocations and inversions with the T-cell receptor genes observed in several post-thymic types of T-cell leukemias and lymphomas, including T-prolymphocytic leukemias (T-PLL) (Brito-Babapulle and Catovsky, 1991, Cancer Genet. Cytogenet. 55:1-9), acute and chronic leukemias associated with the immunodeficiency syndrome ataxia-telangiectasia (AT) (Russo et al., 1988, Cell 53:137-144; Russo et al., 1989, Proc. Natl. Acad. Sci. USA 86:602-606), and adult T-cell leukemia (Virgilio et al., 1993, Proc. Natl. Acad. Sci. USA 90:9275-9279).
Rearrangements of the TCL-1 locus at chromosome 14q32.1 are unique, in that the other locus involved in these rearrangements, namely the TCR α/δ locus, is also on chromosome 14 at subband q11 (Croce et al., 1985, Science 227:1044-1047; Isobe et al., 1988, Proc. Natl. Acad. Sci. USA 85:3933-3937). For this reason, the rearrangements observed cytogenetically are either chromosomal inversions, inv(14) (q11;q32), involving only one of the chromosomes 14 or translocations involving both chromosomes 14 such as the t(14;14) (q11;q32), or more rarely, the t(7:14) (q35;q32) involving the TCR β locus at 7q35 (Isobe et al., 1988, Proc. Natl. Acad. Sci. USA 85:3933-3937). Several of the breakpoints at 14g32.1 involved in these translocations have been cloned and characterized (Russo et al., 1988, Cell 53:137-144; Baer et al., 1987, Proc. Natl. Acad. Sci. USA 84:9069-9073; Mengle-Gaw et al., 1987, EMBO J. 6:2273-2280; Bertness et al., 1990, Cancer Genet. Cytogenet. 44:47-54).
The TCL-1 locus, a chromosomal region of approximately 350 kb as determined by placement of translocation breakpoints on the long range genomic map, has recently been cloned (Virgilio et al., 1993, Proc. Natl. Acad. Sci. USA 90:9275-9279). The involvement of such a large region in translocation events suggests that activation of the putative TCL-1 gene may occur from a distance of many kilobases, as previously observed for the BCL-1/CCND1 gene in mantle cell lymphoma (Tsujimoto et al., 1984, Science 224:1403-1406; Rosenberg et al., 1991, Proc. Natl. Acad. Sci. USA 88:9638-9642; Withers et al., 1991, Mol. Cell. Biol. 11:4846-4853; Motokura and Arnold, 1993, Genes, Chrom. & Cancer 7:89-95) and the MYC oncogene in Burkitt lymphoma (Dalla-Favera et al., 1982, Proc. Natl. Acad. Sci. USA 79:7824-7827; Nishikura et al., 1983, Proc. Natl. Acad. Sci. USA 80:4822-4826) and in acute T-cell leukemia (Erikson et al., 1986, Science 232:884-886).
There remains an unfulfilled need to isolate and characterize the TCL-1 gene associated with chromosomal abnormalities, e.g., chromosomal translocations, inversions and deletions, for use as a diagnostic and therapeutic/prophylactic reagent in the detection, treatment, and prevention of diseases, such as T-cell leukemias and lymphomas, associated with such chromosomal abnormalities.
Citation of references hereinabove shall not be construed as an admission that such references are prior art to the present invention.